1. Field of the Invention
This invention relates to 5-alkylthiophenes, pharmaceutical compositions containing them, and methods of using them to treat inflammation and/or pain in mammals. More particularly this invention relates to antiinflammatory and/or analgesic 5-alkyl-2,3-diarylthiophenes.
2. Prior Art
There is a continuing need for safe and effective antiinflammatory agents to treat inflammation, a disease process characterized by redness, fever, swelling, and pain. Arthritis, in its various forms, is the most prevalent, chronic, and severe of the inflammatory diseases. Traumatic injury and infection also involve inflammation, and antiinflammatory drugs are often used in their treatment as well.
The usefulness of many commercial antiinflammatories, however, is limited because of toxicity and adverse side-effects. Many produce gastric irritation and can cause changes in blood cells or can affect the central nervous system. Adreno-cortical steroids, for example, produce gastric irritation and suppression of normal adrenal function.
The present invention results from efforts to develop new anti-arthritic compounds with good antiinflammatory activity and minimal side effects that could be more effective in treating arthritis than are presently available drugs. In addition to antiinflammatory properties, some compounds of this invention have demonstrated analgesic activity in a test procedure. This additional property is desirable in treatment of arthritis or related diseases; however, such compounds can be employed solely to alleviate pain.
U.S. Pat. No. 3,707,475, (to Pfizer) discloses 2-alkyl-4,5-diarylimidazoles and their use as antiinflammatories. U.S. Pat. No. 3,709,906 (to Sankyo) discloses 2-alkyl-4,5-diarylpyrroles and their use as antiinflammatories. U.S. Pat. Nos. 3,901,908 and 3,929,807 (to Ciba Geigy) disclose 2-alkyl and 2-cycloalkyl-4,5-diarylimidazoles and their use as antiinflammatories. U.S. Pat. Nos. 4,021,553 and 4,190,725 (to Eli Lilly) disclose 5,6-diaryl-3-alkyl-1,2,4-triazines and their use as topical antiinflammatories. Rynbrandt et al., J. Med. Chem., 24, 1507 (1981) disclose 2-alkyl-4,5-diarylthiazoles and their use as platelet aggregation inhibitors.
A number of references including J. L. Melles and H. J. Becker, Rec. Trav. Chim., 72, 314 (1953) and S. Hauptmann and E. M. Werner, J. Prakt. Chem., 314, 499 (1972) describe the preparation of 2,3-diarylthiophenes.
Antiinflammatory and/or analgesic 2,3-diarylthiophenes are described in U.S. Pat. No. 4,302,461, and coassigned U.S. Ser. No. 316,661, filed Nov. 2, 1981, in the name of S. B. Haber, U.S. Ser. No. 295,781, filed Aug. 27, 1981, in the name of S. B. Haber, U.S. Ser. No. 354,300, filed Mar. 3, 1982, in the name of S. B. Haber, and U.S. Ser. No. 354,643, filed Mar. 4, 1982, in the name of S. B. Haber. None has an alkyl substituent at the 5-position.
G. N. Schrauzer and V. P. Mayweg, J. Am. Chem. Soc., 87, 1483-9 (1965) report 2,3-dimethyl-4,5-diphenylthiophene. No biological activity is disclosed.
R. E. Atkinson and F. E. Hardy, J. Chem. Soc. Perkin II, 27-30 (1972) report 5,5'-dimethyl-3-(2-benzimidazolyl)-2,2'-bithienyl and the 3-(2-indolyl) derivative, prepared in the course of fluorescence studies. ##STR1##